Antidiabetic effects of the Cimicifuga racemosa extract Ze 450 in vitro and in vivo in ob/ob mice.

INTRODUCTION: It was the aim of the present experiments to examine potential antidiabetic effects of the Cimicifuga racemosa extract Ze 450. METHODS: Ze 450 and some of its components (23-epi-26-deoxyactein, protopine and cimiracemoside C) were investigated in vitro for their effects on AMP-activated protein kinase (AMPK) compared to metformin in HepaRG cells. Ze 450 (given orally (PO) and intraperitonally (IP)), metformin (PO) and controls were given over 7 days to 68 male ob/ob mice. Glucose and insulin concentrations were measured at baseline and during an oral glucose tolerance test (OGTT). RESULTS: Ze 450 and its components activated AMPK to the same extent as metformin. In mice, Ze 450 (PO/IP) decreased significantly average daily and cumulative weight gain, average daily food and water intake, while metformin had no effect. In contrast to metformin, PO Ze 450 virtually did not change maximum glucose levels during OGTT, however, prolonged elimination. Ze 450 administered PO and IP decreased significantly post-stimulated insulin, whereas metformin did not. HOMA-IR index of insulin resistance improved significantly after IP and PO Ze 450 and slightly after metformin. In summary, the results demonstrate that Ze 450 reduced significantly body weight, plasma glucose, improved glucose metabolism and insulin sensitivity in diabetic ob/ob mice. In vitro experiments suggest that part of the effects may be related to AMPK activation. CONCLUSIONS: Ze 450 may have utility in the treatment of type 2 diabetes. However, longer term studies in additional animal models or patients with disturbed glucose tolerance or diabetes may be of use to investigate this further.

Lisdexamfetamine and immediate release d-amfetamine - differences in pharmacokinetic/pharmacodynamic relationships revealed by striatal microdialysis in freely-moving rats with simultaneous determination of plasma drug concentrations and locomotor activity.

Lisdexamfetamine mesylate (Vyvanse(®)) is a novel prodrug approved for attention deficit hyperactivity disorder (ADHD). It is metabolised to d-amfetamine and l-lysine. In drug-experienced humans, lisdexamfetamine evoked lower "Drug liking" scores on Drug Rating Questionnaire (DRQ) scales than immediate-release (IR) d-amfetamine. This study investigated why lisdexamfetamine may have lower abuse potential and a better therapeutic window than d-amfetamine. We compared the pharmacokinetic/pharmacodynamic relationships of lisdexamfetamine and IR d-amfetamine in freely-moving rats by measuring simultaneously extracellular concentrations of striatal dopamine, plasma concentrations of d-amfetamine and lisdexamfetamine, and locomotor activity. At equivalent doses (1.5 mg/kg d-amfetamine base), lisdexamfetamine produced smaller, but more sustained, increases in striatal dopamine efflux than d-amfetamine and substantially less locomotor activation. Consistent with it being a prodrug, increased striatal dopamine and locomotion correlated with plasma concentration of its metabolite, d-amfetamine, but not the parent compound. Compared with IR d-amfetamine, lisdexamfetamine produced an identical AUC for plasma d-amfetamine, but a 50% lower C(max) and significantly delayed t(max). Where a hysteresis relationship did exist between plasma concentrations of d-amfetamine and striatal dopamine or locomotor activity, they were anticlockwise in direction for lisdexamfetamine and IR d-amfetamine. For extracellular striatal dopamine (neurochemical mediator) and locomotor activity (functional outcome), it was anticlockwise for lisdexamfetamine, but clockwise for IR d-amfetamine. This shows that lisdexamfetamine produced less pronounced behavioural activation as dopamine concentrations increased, but activity was maintained for longer when they declined. These findings help explain why the unusual pharmacokinetics of lisdexamfetamine evoked lower "Drug liking" scores than IR d-amfetamine and also suggest therapeutic window between efficacy and stimulant side-effects will be larger.

Metachronous squamous-cell carcinoma of the colon and treatment of rectal squamous carcinoma with chemoradiotherapy.

Rectal squamous-cell carcinoma is a rare tumour with an incidence of less than 1 per 1000 cases. We report such a case treated with chemoradiotherapy. The patient developed a metastasis in the spleen and a further squamous tumour in the right colon, both of which were successfully resected. No histological evidence of recurrent rectal tumour has been found. Two years following presentation, the patient remains disease-free although symptomatic from a radiotherapy-induced stricture of the rectum.

Endostatin expression in a pancreatic cell line is modulated by a TNFalpha-dependent elastase.

Endostatin, an inhibitor of angiogenesis, is a 20 kDa fragment of the basement membrane protein, collagen XVIII. The formation of endostatin relies upon the action of proteases on collagen XVIII. TNFalpha, produced by activated macrophages, is a multifunctional proinflammatory cytokine with known effects on endothelial function. We postulated that TNFalpha may modulate the activities of proteases and thus regulate endostatin formation in pancreatic cells. Collagen XVIII/endostatin mRNA was expressed in one pancreatic cell line, SUIT-2, but not in BxPc-3. The 20 kDa endostatin was found in the cell-conditioned medium of SUIT-2 cells. Precursor forms only were found in the cells. Exogenous endostatin was degraded by cellular lysates of SUIT-2 cells. Elastase activity was found in cell extracts but not the cell-conditioned media of SUIT-2 cells. Incubation of SUIT-2 cells with TNFalpha increased intracellular elastase activity and also increased secretion of endostatin into the medium. We conclude that endostatin is released by SUIT-2 cells and that increases in intracellular elastase, induced by TNFalpha, are correlated with increased secretion. Endostatin is however susceptible to degradation by intracellular proteases and if tissue injury accompanies inflammation, endostatin may be degraded, allowing angiogenesis to occur.

Endostatin expression in pancreatic tissue is modulated by elastase.

Pancreatic tumours are scirrhous, avascular tumours, suggesting that they may produce angiogenesis inhibitors that suppress the growth of the vasculature to the tumour and metastases. We have sought evidence for the angiogenesis inhibitor, endostatin, in normal and cancerous pancreatic tissue. Using Western blotting, we found mature 20 kDa endostatin in cancer tissue but not in normal tissue. Several endostatin-related peptides of higher mol wt were present in both tissues. Extracts from normal tissue were able to degrade exogenous endostatin, whereas extracts from cancer were without effect. Although the exocrine pancreas secretes inactive proenzymes of trypsin, chymotrypsin and elastase, their possible role in this degradation was examined. The trypsin/chymotrypsin inhibitor, Glycine max, did not prevent the degradation of endostatin by normal pancreatic extracts but elastatinal, a specific inhibitor of elastase, reduced the rate of degradation. Extracts of pancreatic tumours did not express any detectable elastase activity, but an elastase (Km 1.1 mM) was expressed by extracts of normal pancreas. We conclude that endostatin is present and stable in pancreatic cancer tissues, which may explain their avascular nature, but that normal pancreatic tissue expresses enzymes, including elastase, which rapidly degrade endostatin. The stability of endostatin may have implications for its therapeutic use.

A 10-year experience of complex liver trauma.

BACKGROUND: Liver trauma is a relatively rare surgical emergency but mortality and morbidity rates remain significant. It is likely that surgeons outside specialist centres will have limited experience in its management; therefore best practice should be identified and a specialist approach developed. METHODS: Data collected from 52 consecutive patients over a 10-year interval were examined to identify best practice in the management of these injuries. RESULTS: The majority of injuries occurred as a result of road traffic accidents; 39 (75 per cent) of the 52 patients were stable at presentation to the referring hospital. In 36 patients (69 per cent) the liver injury was a component of multiple trauma. Ultrasonography, computed tomography or no radiological investigation was used in the referring hospital in 18 (35 per cent), 25 (48 per cent) and nine (17 per cent) patients respectively. Operative management was undertaken in the referring hospital in 26 patients (50 per cent). The overall mortality rate was 23 per cent (12 of 52 patients), and increased with increasing grade of severity. Eight of 26 patients managed surgically at the referring hospital died, compared with four of the 26 patients managed without operation (P not significant). The median time from arrival at the referring hospital to operation was 4 h for haemodynamically stable patients and 3 h for those who were haemodynamically unstable. CONCLUSION: Most patients with liver trauma can be managed conservatively. Operative management carried out in non-specialized units is associated with high mortality and morbidity rates. Abdominal injuries should raise a high index of suspicion of liver injury, and the data suggest that computed tomography of the abdomen should precede laparotomy (even in some haemodynamically unstable patients) to facilitate discussion with a specialist unit at the earliest opportunity.

Determination of body composition in conscious adult female Wistar utilising total body electrical conductivity.

Total body electrical conductivity (TOBEC) is a noninvasive method for estimating fat free mass (FFM) in live animals. In this study, we have evaluated the use of the Em-Scan SA-3000, which is claimed by the manufacturers to perform better than earlier analysers. Previous studies in rats using these earlier versions of the TOBEC analyser have always used anaesthesia to minimise movement artefacts. As repeated anaesthesia also has the potential to induce artefacts by disrupting food intake, for example, we have also attempted to determine if this TOBEC analyser can be used to predict body composition in conscious adult weight-stable female Wistar rats. A simplified cafeteria diet was used to produce large variations in body composition (40-350 g fat/carcass) and a full chemical body composition analysis was performed to generate a TOBEC calibration equation. The TOBEC parameter was more strongly correlated to FFM (r(2)=.785) than it was to body weight (r(2)=.669) or other body composition parameters. Using the TOBEC calibration equation to predict fat mass on these data, there was an excellent correlation with the value obtained by chemical analyses (r(2)=.952, slope=0.958). To determine if the TOBEC calibration equation derived from this calibration study would then be useful for the routine estimation of body composition an additional, validation study was performed. This validation study was performed 6 months later, used an independent group of obese female Wistar rats and was undertaken by different TOBEC operators. This validation study, again, showed a good correlation between the TOBEC- and chemical-derived fat mass (r(2)=.918, slope=1.003) indicating stability of the calibration equation with time and independence from operator. We therefore conclude that it is possible to meaningfully estimate body fat changes in conscious rats using this TOBEC analysis system.

Advances in non-operative therapy in pancreatic cancer.

Pancreatic cancer is the fifth leading cause of cancer death in the western world. The majority of patients present with advanced disease and only a few have resectable disease at presentation. This paper reviews current evidence supporting the use of conventional chemotherapy and radiotherapy in advanced disease; it goes on to review the rationale and how these data have influenced the use of radiochemotherapy in the adjuvant setting. Unpublished data from the largest adjuvant study of chemoradiotherapy in pancreatic cancer are also presented. The role of neoadjuvant therapy is discussed and how trials using this approach are evolving in pancreatic cancer. The paper finishes by reviewing the use of marimastat, a novel agent that has been extensively studied in patients with pancreatic cancer. Pancreatic cancer remains a challenge to clinicians, but increases in sub-specialisation and a renewed interest in the disease has made the future for patients more encouraging than at any time in the past.

Wound healing: effects of closing tension, zyplast, and platelet-derived growth factor.

Previous studies have shown that beginning 5 to 7 days from wounding, the tensile strength of wounds closed under tension in rats is significantly higher than the tensile strength of wounds closed without tension. This study evaluated the effects of increased closing tension, zyplast implant (ZI), and human recombinant platelet-derived growth factor (PDGF) on the tensile strength of wounds. Six groups of 12 rats each were divided into two main subsets: wounds were closed without tension in three groups and with high tension of approximately 100 g in the three other groups. In both no-tension and high-tension groups, one subgroup received no intervention (controls), one subgroup received ZI (zyplast controls), and one subgroup received ZI-PDGF (ZI used as a carrier for PDGF). Healing was evaluated by tensile strength determinations at 5 days. For the controls, wounds closed under tension showed a trend toward higher tensile strength, but statistical significance was not reached. Compared with controls, tensile strength was 45% lower in the wounds with ZI and closure with tension (P = .0063) and 38% lower in the wounds with ZI and closure without tension (P = .007). Treatment with ZI-PDGF resulted in 69% higher tensile strengths (P = .049) as compared with ZI controls for wounds closed with tension. This study demonstrated the beneficial effect of PDGF in accelerating healing in wounds closed under tension. Although ZI was able to deliver PDGF to the wound, the use of this substance as a carrier is questioned since it was detrimental to healing.

Use of Proplast II as a subperiosteal implant for the correction of anophthalmic enophthalmos.

BACKGROUND: A variety of autogenous and alloplastic materials have been used as subperiosteal implants to correct anophthalmic enophthalmos. Proplast II is a synthetic porous composite of Teflon polymer and alumina. Proplast II offers a number of advantages over other commonly used alloplastic materials such as silicone and polymethyl methacrylate. It is light, porous, resilient, malleable, and easy to shape. It can be readily sterilised after shaping. It has been found to integrate with the surrounding tissues, thereby minimising the risk of subsequent implant migration and extrusion. METHODS: Proplast II was used as a subperiosteal implant in a total of 15 anophthalmic patients during the period June 1990 to March 1994. The indication for this procedure in all patients was poor orbital volume replacement despite the prior insertion of an adequately sized spherical socket implant. RESULTS: The results were excellent with a good correction of preoperative upper eyelid sulcus deformity. There were no operative complications nor any serious postoperative complications. The implants were well tolerated. CONCLUSION: Proplast II can be highly recommended for use as a subperiosteal implant.

Adult rhabdomyoma of the larynx.

Rhabdomyomas of the larynx are rare lesions, with the "adult" type occurring more frequently than the "fetal" type. Treatment is complete surgical removal. Recurrences would suggest an incomplete surgical procedure and/or an incorrect pathological diagnosis.

Investigation of an expert systems approach to bacterial identification.

An investigation was carried out to assess the feasibility of using an expert systems approach to assist in the identification of unknown isolates of bacteria. A system was developed using Lisp which utilized the knowledge stored in standard bacteriological texts. A comparison of the expert systems approach and the probabilistic approach based on Bayes Theorem was made together with the advantages and disadvantages of each approach.

Charge Coupled Device (CCD) Area Detector for On-Line (40- to 80-ms) Acquisition of Laue Diffraction Data from Protein Crystals.

A direct charge coupled device (CCD) detector has been used to record Laue diffraction data from a protein crystal illuminated with a synchrotron radiation beam of continuous wavelengths 0.2 Å < λ < 2.5 Å. The exposure time used to record the data was 40-80 ms. The point spread factor of the detector was negligible. The sensitivity of CCD detectors at high photon energies is discussed in relation to other electronic area detector schemes. The lack of fine energy resolution of this or any other electronic area detector is not considered a limiting factor because of the high proportion of spots of single wavelength arising from single reciprocal lattice points. A time-resolved study of radiation damage to a crystal of concanavalin A was performed.

Glomus tumors of the temporal bone: contemporary evaluation and therapy.

Surgical management of glomus tumors of the temporal bone requires accurate preoperative assessment and a knowledge of temporal bone anatomy, contemporary microsurgical techniques, and appropriate postoperative management. Care should be exercised to minimize postoperative neurologic deficit and deformity resulting from surgery of this usually benign lesion. The primary preoperative goal is to determine the extent of the lesion; although the history and physical examination are helpful, radiologic delineation of the tumor is imperative. Recent advances in surgical approaches and techniques have allowed the removal of larger tumors with lessened mortality and morbidity. Our overall experience in this series of glomus tumors leads us to believe that surgical excision is the treatment of choice for the treatment of glomus tumors of the temporal bone.

Pitfalls in the diagnosis of acoustic neuroma.

The patient with an acoustic neuroma may present to the otologist with a variety of clinical features. Classically these include a retrocochlear pattern of sensorineural hearing loss, reduced vestibular response on caloric testing and radiological asymmetry of the internal auditory canals (IAC). The absence of any or all of these features, however, does not exclude the presence of tumour. Five cases are presented to illustrate the potential for diagnostic delay unless a routine battery of investigations is undertaken in patients with neuro-otological disorders. All patterns of subjective audiometry are encountered, auditory brain stem response testing may be unreliable where hearing loss is profound, vestibular testing is normal in half of small tumours and the intracanalicular tumour may be radiologically undetectable unless IAC meatography is employed.